Hereditary transthyretin amyloidosis in the era of RNA interference, antisense oligonucleotide & CRISPR-Cas9 treatments.

Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant adult-onset disorder caused by point mutations in the transthyretin (TTR) gene encoding TTR, i.e., prealbumin. ATTRv survival ranges from 3 to 10 years, and peripheral nervous system and heart are usually the two main tissues affected, although central nervous system and eye may also be involved. As liver is the main TTR protein secretor organ, it has been the main target of treatments developed these last years, including liver transplantation (LT) which has been shown to significantly increase survival in a subset of patients carrying the so-called "early-onset Val30Met" TTR gene mutation. More recently, treatments targeting hepatic TTR RNA have been developed. Hepatic TTR RNA targeting is performed using RNA interference (RNAi) and antisense oligonucleotide (ASO) technologies involving lipid nanoparticle carriers or Gal-NAC fragments. RNAi and ASO treatments induce an 80% decrease in TTR liver production for a period of 1-12 weeks. ASO and RNAi phase III trials in patients with TTR-related polyneuropathy have shown a positive impact on neuropathy clinical scores and quality of life endpoints, and delayed RNAi treatment negatively impacts survival. Clinical trials specifically investigating RNAi therapy in TTR cardiomyopathy are underway. Hepatic RNA targeting has revolutionized ATTRv treatment and may allow transforming a fatal disease into a treatable disorder. As retina and choroid plexus secrete limited quantities of TTR protein, both tissues are now seen as the next targets for fully controlling the disease.